Various amino peptidases are present in the mammals and catalyze the sequential release of peptidase from peptides such as, pyroglutamyl aminopeptidase and prolylaminpeptidase in addition to dipeptidyl peptidase. Dipeptidyl peptidase family includes DP II, DP-IV, DP VIII, DP IX. (Curr. Opin. Chem. Biol. 2003, 7, 496) The newly synthesized compounds provide DP-IV inhibition activity sufficiently fast and target rate. The enzyme DP-IV is a part of the CD26 surface region associated with immune regulation, signal transduction and apoptosis. DP-IV enzyme works as a suppressor in the development of cancer and tumours. DP-IV also plays major role in glucose metabolism and responsible for the degradation of incretins such as Glucagon-like peptide-1 (GLP-1). GLP-1 is an incretin hormon secreted by intestinal L-cells in response to food intake. The active form of GLP-1 is having 30-aminoacid peptide, which stimulates insulin, release, inhibits glucagons release, and slows gastric emptying, each a benefit in control of glucose homeostasis in patients with type II diabetes. The activation of GLP-1 is rapidly inactivated by the plasma DP-IV which cleaves a dipeptide from a N-terminal. (Eur. J. Biochem., 1993, 214, 829 and Endocrinology 1995, 136, 3585). DP-IV inhibitors offers several potential advantages over existing therapies including decreased risk of hypoglycemia, potential weight loss, and the potential for regeneration and differentiation of pancreatic β-cells. DP-IV also binds to the enzyme adenosine deaminase specifically and with high affinity.
Casomorphin is a particular type of peptide which is protein fragment. Casomorphin can be derived from the digestion of casein proteins in milk and milk products. The most important casomorphins from bovine milk are those released from the digestion of β-casomorphins, sometimes denoted as BCM followed by numeral indicating the number of amino acids in the sequence. The potential release of β-casomorphins varies between species and breeds. Casomorphin is a series of peptides ranging from 3 to 8 amino acids. In present invention, we explore the synthesis of peptide derivatives based on amino acid sequencing of Casomorphin peptides. The different peptides derivatives ranging from 2 to 20 amino acids are synthesized using substituted amine derivatives.
Several DP-IV inhibitors possessing modified proline structure as P2 moiety have been reported as illustrated below. (Bioorg. Med. Chem. Lett. 2008, 16, 190)                In 2005, Sakashita et al., disclosed that (4-substituted)-L-prolyl-(2S)-2-cyanopyrrolidine showed increased inhibition of DP-IV activity relative to unsaturated analogs and that (4β-substituted)-L-prolyl-(2S)-2-cyanopyrrolidine showed 20-fold stronger activity than the corresponding 4α isomer. (Bioorg. Med. Chem. Lett. 2005, 15, 2441)        Tsai et al. disclosed that (4βcarbamoyl)-L-prolyl-(2S)-2-cyanopyrrolidine showed enhanced DP-IV inhibition activity, while (5,5-gem-dimethyl)-L-prolyl-(2S)-2-cyanopyrrlidine showed as 500 fold decrease of DP-IV inhibition relative to the unsubstituted analog. (Bioorg. Med. Chem. Lett. 2006, 16, 3268)        Heins, J. et al discloses that DP-IV is a serine protease that catalyzes the cleavage of dipeptides from the N-terminus of proteins with the sequence H-X-Pro-Y or H-X-Ala-Y (where X,Y=any amino acid, Y≠Pro.) (Biochim. Biophys. Acta., 1988, 954, 161)        